In a healthy person, the blood glucose (“BG”) level is internally regulated through insulin released from the pancreas that counterbalances carbohydrate intakes from food, drinks, etc. Because patients with Type 1 Diabetes Mellitus (“T1DM”) are unable to produce sufficient amounts of insulin, this internal self-regulation is disrupted. The standard daily control of T1 DM involves multiple insulin injections, or a continuous insulin infusion using an insulin pump, that lowers BG. However, this external BG control is not nearly as precise or reliable as the internal self-regulation, e.g., too little insulin results in chronic high BG levels, too much can cause hypoglycemia.
Extensive recent studies have demonstrated that the most effective long-term control of T1DM results from the strict maintenance of BG levels within a normal range through intensive insulin therapy. Detailed results were presented by the 10-year Diabetes Control and Complications Trial (“DCCT”) and its European counterpart. See The Diabetes Control and Complications Trial Research Group, “The effect of intensive treatment of diabetes on the development and progression of long-term complications of insulin-dependent diabetes mellitus,” NEJM, 329: 978-86 (1993); Reichard P, et al., “Mortality and treatment side-effects during long-term intensified conventional insulin treatment in the Stockholm Diabetes Intervention study,” Diabetes, 43: 313-17 (1994).
The DCCT proved that chronic high BG levels cause many complications in multiple body systems over time, while too much insulin results in hypoglycemia. Without immediate treatment, hypoglycemia can rapidly progress to severe hypoglycemia (“SH”), a condition identified by low BG resulting in stupor, seizure or unconsciousness that precludes self-treatment. If the patient does not receive treatment during an SH episode, death can occur. Approximately 4% of deaths in T1DM patients are attributed to SH. In short, while on one hand, intensive therapy is the best long-term treatment of T1DM, on the other it has been associated with at least a threefold increase in SH.
Since SH can result in accidents, coma and even death, it discourages patients and health care providers from pursuing intensive therapy. Consequently, hypoglycemia has been identified as a major barrier to improved glycemic control. See Cryer P E, “Hypoglycemia begets hypoglycemia,” Diabetes, 42: 1691-93 (1993); Cryer P E, et al., “Hypoglycemia” Diabetes Care 17: 734-55 (1994). In other words, patients with T1DM face a life-long clinical optimization problem, i.e., to maintain strict glycemic control without increasing risk for hypoglycemia. A bio-mathematical problem associated with this optimization is to create a quantitative procedure that would continuously assess the risk of hypoglycemia, thus providing means for external regulation of BG within optimal limits.
A significant problem with such an approach is the detection of hypoglycemia prior to the development of neurogenic symptoms. Numerous studies have investigated the occurrence of hypoglycemia-related symptoms and generally found that such warning signs occur and are recognized by patients in less than 50% of all hypoglycemic episodes and are associated with quite low BG levels of 70 mg/dl and below. See Boyle P J, et al., “Plasma glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly-controlled diabetes and in nondiabetics,” NEJM, 318: 1487-92 (1988); Clarke W L, et al., “Multifactorial origin of hypoglycemic symptoms unawareness in IDDM: Association with defective glucose counterregulation and better glycemic control,” Diabetes. 40: 680-85 (1991); Clarke W L, et al., “Reduced awareness of hypoglycemia in IDDM adults: A prospective study of hypoglycemia frequency and associated symptoms,” Diabetes Care, 18: 517-22 (1995); Cox D J, et al., “Perceived symptoms in the recognition of hypoglycemia,” Diabetes Care, 16: 519-27 (1993); Cox D J, et al., “Sex differences in BG thresholds for counterregulatory hormone release and low blood glucose symptom perception,” Diabetes Care, 19: 269-70 (1996).
This means that about half of all hypoglycemic episodes are asymptomatic, or unrecognized, and even if recognized in many cases represent dangerously low BG levels. Reliable automated recognition of upcoming hypoglycemia would allow for intensified insulin therapy with reduced fear of hypoglycemia. The benefit of such a strategy includes reduced damage to eyes, nerves, kidneys and blood vessels of diabetics, lower health care costs and reduced morbidity and mortality in T1DM cases.
Efforts to predict hypoglycemia have not been effective in the past, and attempts to predict a patient's vulnerability to SH have been particularly unsuccessful. Various approaches to assess the risk of SH have been tested, including low HbA1c, intensive therapy, inadequate hormonal counter-regulation, hypoglycemia unawareness, and a history of SH. For instance, the DCCT (with intensive therapy) demonstrated that only about 8% of future SH could be predicted from known variables. See “The DCCT Research Group: Epidemiology of severe hypoglycemia in the diabetes control and complications trial,” Am. J. Med, 90: 450-59 (1991).
A recent structural equation model accounted for 18% of the variance of SH using historv of SH, hypoglycemia awareness and autonomic score. See Gold A E, et al, “A structural equation model for predictors of severe hypoglycemia inpatients with insulin-dependent diabetes mellitus,” Diabetic Med., 14: 309-15 (1997).
Another mathematical model was developed taking the patient's diet, medication and physical strain into account to provide predictive blood glucose values. See U.S. Pat. No. 5,840,020 to Heinonen, et al. A diabetes management system for predicting future blood glucose concentrations based upon current blood glucose concentrations and the insulin action remaining from previous insulin doses has also been proposed. See U.S. Pat. No. 5,822,715 to Worthington, et al.
However, none of these models accurately predict the risk of SH or the onset of hypoglycemia.